Cyclophosphamide enhances anti-tumor effects of a fibroblast activation protein α-based DNA vaccine in tumor-bearing mice with murine breast carcinoma
Cyclophosphamide enhances anti-tumor effects of a fibroblast activation protein α-based DNA vaccine in tumor-bearing mice with murine breast carcinoma
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DOI：
10.1080/08923973.2016.1269337
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发表时间：
2017-01
影响因子：
3.3
通讯作者：
Q. Xia;F. Geng;Fangfang Zhang;Chenlu Liu;P. Xu;Zhenzhen Lu;Yu Xie;Bo Sun;H. Wu;Bin Yu;W. Kong;Xianghui Yu;Hai-hong Zhang
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文献类型：
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作者：
Q. Xia;F. Geng;Fangfang Zhang;Chenlu Liu;P. Xu;Zhenzhen Lu;Yu Xie;Bo Sun;H. Wu;Bin Yu;W. Kong;Xianghui Yu;Hai-hong Zhang
摘要环磷酰胺（CY）是一种DNA烷基化剂，与其他化疗药物一起广泛应用于各种癌症的治疗。它不仅可用作化疗药物，而且可用作免疫调节剂以抑制IL-10表达和调节性T细胞（T细胞）。成纤维细胞活化蛋白α（FAPα）在肿瘤微环境中的癌症相关成纤维细胞中表达。基于FAPα作为肿瘤基质抗原的免疫治疗通常诱导靶向肿瘤微环境的特异性免疫应答。本研究评估了先前未报道的CY组合策略增强靶向FAPα的DNA疫苗的有限抗肿瘤作用的有效性。结果表明，环磷酰胺能提高脾脏中CD 8 + T细胞的比例，降低脾脏中CD 4 + CD 25 + Foxp 3 + T细胞的比例。在肿瘤组织中，包括IL-10和CXCL-12在内的免疫抑制细胞因子水平也降低。同时，CY联合应用不损害DNA疫苗诱导的FAPα特异性免疫，并进一步降低肿瘤间质因子。最重要的是，也用CY化疗处理的FAP接种的小鼠显示出对肿瘤生长的显著抑制（抑制率=80%）和存活时间的延长。因此，FAPα免疫治疗和化疗与CY的组合为改善癌症治疗提供了新的见解。
Abstract Cyclophosphamide (CY) is a DNA alkylating agent, which is widely used with other chemotherapy drugs in the treatment of various types of cancer. It can be used not only as a chemotherapeutic but also as an immunomodulatory agent to inhibit IL-10 expression and T regulatory cells (Tregs). Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts in the tumor microenvironment. Immunotherapy based on FAPα, as a tumor stromal antigen, typically induces specific immune response targeting the tumor microenvironment. This study evaluated the efficacy of a previously unreported CY combination strategy to enhance the limited anti-tumor effect of a DNA vaccine targeting FAPα. The results suggested CY administration could promote the percentage of splenic CD8+ T cells and decrease the proportion of CD4 + CD25 + Foxp3+ Tregs in spleen. In tumor tissues, levels of immunosuppressive cytokines including IL-10 and CXCL-12 were also reduced. Meanwhile, the CY combination did not impair the FAPα-specific immunity induced by the DNA vaccine and further reduced tumor stromal factors. Most importantly, FAP-vaccinated mice also treated with CY chemotherapy showed a marked suppression of tumor growth (inhibition ratio =80%) and a prolongation of survival time. Thus, the combination of FAPα immunotherapy and chemotherapy with CY offers new insights into improving cancer therapies.